Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Persistent breast pain in post-surgery breast cancer survivors and women with no history of breast surgery or cancer: associations with pain catastrophizing, perceived breast cancer risk, breast cancer worry, and emotional distress.

Background: Persistent breast pain (PBP) is prevalent among breast cancer survivors and has powerful negative psychological consequences. The present study provided a first test of the hypothesis that: (a) pain catastrophizing, (b) heightened perceived risk of cancer, and (c) worry that pain indicates cancer may be independent mediating links between breast cancer survivors' experiences of PBP and heightened emotional distress. Methodology: We assessed levels of PBP and psychological factors in breast cancer survivors (Survivor Group: n = 417; Stages I-IIIA; White = 88.7%; Age M = 59.4 years) at their first surveillance mammogram post-surgery (6-15 months). A comparison group of women without histories of breast surgery or cancer (Non-cancer Group: n = 587; White = 78.7%; Age M = 57.4 years) was similarly assessed at the time of a routine screening mammogram. All women completed measures of breast pain, pain catastrophizing, perceived breast cancer risk, and worry that breast pain indicates cancer, as well as measures of emotional distress (symptoms of anxiety, symptoms of depression, and mammography-specific distress). Analyses included race, age, BMI, education, and menopausal status as covariates, with significance set at 0.05. Results: As expected, PBP prevalence was significantly higher in the Survivor Group than in the Non-cancer Group (50.6% vs. 17.5%). PBP+ survivors also had significantly higher levels of emotional distress, pain catastrophizing, mammography-specific distress, and worry that breast pain indicates cancer, compared to PBP- survivors. Structural equation modeling results were significant for all hypothesized mediational pathways. Interestingly, comparisons of PBP+ to PBP- women in the Non-cancer Group showed similar results. Conclusion: These findings suggest the importance of (a) pain catastrophizing, (b) perceived breast cancer risk and, (c) worry that breast pain may indicate cancer, as potential targets for interventions aimed at reducing the negative psychological impact of PBP in post-surgery breast cancer survivors, as well as in unaffected women with PBP due to unknown reasons.

Axillary Ultrasound Identifies Residual Nodal Disease After Chemotherapy: Results From the American College of Surgeons Oncology Group Z1071 Trial (Alliance).

OBJECTIVE: The purpose of this study is to determine lymph node features on axillary ultrasound (US) images obtained after neoadjuvant chemotherapy that are associated with residual nodal disease in patients with initial biopsy-proven node-positive breast cancer. SUBJECTS AND METHODS: All patients had axillary US performed after neoadjuvant chemotherapy. Axillary US images were centrally reviewed for lymph node size, cortical thickness, and cortical morphologic findings (type I indicated no visible cortex; type II, a hypoechoic cortex ≤ 3 mm; type III, a hypoechoic cortex > 3 mm; type IV, a generalized lobulated hypoechoic cortex; type V, focal hypoechoic cortical lobulation; and type VI, a totally hypoechoic node with no hilum). Lymph node characteristics were compared with final surgical pathologic findings. RESULTS: Axillary US images obtained after neoadjuvant chemotherapy and surgical pathologic findings were available for 611 patients. Residual nodal disease was present in 373 patients (61.0%), and 238 (39.0%) had a complete nodal pathologic response. Increased cortical thickness (mean, 3.5 mm for node-positive disease vs 2.5 mm for node-negative disease) was associated with residual nodal disease. Lymph node short-axis and long-axis diameters were significantly associated with pathologic findings. Patients with nodal morphologic type I or II had the lowest rate of residual nodal disease (51 of 91 patients [56.0%] and 138 of 246 patients (56.1%), respectively), whereas those with nodal morphologic type VI had the highest rate (44 of 55 patients [80.0%]) (p = 0.004). The presence of fatty hilum was significantly associated with node-negative disease (p = 0.0013). CONCLUSION: Axillary US performed after neoadjuvant chemotherapy is useful for nodal response assessment, with longer short-axis diameter, longer long-axis diameter, increased cortical thickness, and absence of fatty hilum significantly associated with residual nodal disease after neoadjuvant chemotherapy.

Magee Equation 3 predicts pathologic response to neoadjuvant systemic chemotherapy in estrogen receptor positive, HER2 negative/equivocal breast tumors.

Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equation 3 utilizes immunohistochemical and FISH data for estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 for its calculation (24.30812+ERIHC × (-0.02177)+PRIHC × (-0.02884)+(0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive)+Ki-67 × 0.18649). We hypothesize that Magee Equation 3 scores from pre-therapy core biopsy can predict response to neoadjuvant systemic chemotherapy. A prospectively-maintained database of patients who received neoadjuvant systemic therapy from 2010 to 2014 at a single institution was retrospectively reviewed. Pathologic complete response was defined as absence of invasive tumor in the breast and regional lymph nodes. Of the 614 cases, tumors with missing immunohistochemical results and those that were ER negative or HER2 positive were excluded. This resulted in 237 ER positive, HER2 negative/equivocal tumors that formed the basis of this study. Magee Equation 3 scores were divided into 3 categories similar to Oncotype DX, ie, 0 to <18 (low), 18 to <31 (intermediate), and 31 or higher (high) scores. The pathologic complete response rate for low, intermediate and high Magee Equation 3 scores was 0%, 4%, and 36%, respectively. Patients with high Magee Equation 3 scores were 13 times more likely to achieve pathologic complete response compared to those with Magee Equation 3 scores less than 31 (95% CI 5.09-32.87, P<0.0001). For patients that did not achieve pathologic complete response, high Magee Equation 3 correlated with higher recurrence rate, with the majority occurring in patients with positive lymph nodes in the resection specimen. Magee Equation 3 score ≥31 predicts pathologic complete response in the neoadjuvant setting and for tumor recurrence, when pathologic complete response is not achieved. These results show the utility of Magee Equation 3 in predicting patients who will benefit from chemotherapy but warrant prospective multi-institutional validation.

Identification and Resection of Clipped Node Decreases the False-negative Rate of Sentinel Lymph Node Surgery in Patients Presenting With Node-positive Breast Cancer (T0-T4, N1-N2) Who Receive Neoadjuvant Chemotherapy: Results From ACOSOG Z1071 (Alliance).

BACKGROUND: The American College of Surgeons Oncology Group Z1071 trial reported a false-negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. One proposed method to decrease the FNR is clip placement in the positive node at initial diagnosis with confirmation of clipped node resection at surgery. METHODS: Z1071 was a multi-institutional trial wherein women with clinical T0-T4,N1-N2,M0 breast cancer underwent SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. In cases with a clip placed in the node, the clip location at surgery (SLN or ALND) was evaluated. RESULTS: A clip was placed at initial node biopsy in 203 patients. In the 170 (83.7%) patients with cN1 disease and at least 2 SLNs resected, clip location was confirmed in 141 cases. In 107 (75.9%) patients where the clipped node was within the SLN specimen, the FNR was 6.8% (confidence interval [CI]: 1.9%-16.5%). In 34 (24.1%) cases where the clipped node was in the ALND specimen, the FNR was 19.0% (CI: 5.4%-41.9%). In cases without a clip placed (n = 355) and in those where clipped node location was not confirmed at surgery (n = 29), the FNR was 13.4% and 14.3%, respectively. CONCLUSIONS: Clip placement at diagnosis of node-positive disease with removal of the clipped node during SLN surgery reduces the FNR of SLN surgery after neoadjuvant chemotherapy. Clip placement in the biopsy-proven node at diagnosis and evaluation of resected specimens for the clipped node should be considered when conducting SLN surgery in this setting.

Axillary Staging After Neoadjuvant Chemotherapy for Breast Cancer: A Pilot Study Combining Sentinel Lymph Node Biopsy with Radioactive Seed Localization of Pre-treatment Positive Axillary Lymph Nodes.

BACKGROUND: Neoadjuvant chemotherapy (NAC) downstages axillary disease in 55 % of node-positive (N1) breast cancer. The feasibility and accuracy of sentinel lymph node biopsy (SLNB) after NAC for percutaneous biopsy-proven N1 patients who are clinically node negative (cN0) by physical examination after NAC is under investigation. ACOSOG Z1071 reported a false-negative rate of <10 % if ≥3 nodes are removed with dual tracer, including excision of the biopsy-proven positive lymph node (BxLN). We report our experience using radioactive seed localization (RSL) to retrieve the BxLN with SLNB (RSL/SLNB) for cN0 patients after NAC. METHODS: We performed a retrospective review of a single-institution, prospectively maintained registry for the years 2013 to 2014. Patients with BxLN who received NAC and had RSL/SLNB were identified. All BxLNs were marked with a radiopaque clip before NAC to facilitate RSL. RESULTS: Thirty patients with BxLN before NAC were cN0 after NAC and underwent RSL/SLNB. Median age was 55 years. Disease stage was IIA-IIIB. Twenty-nine of 30 had ductal cancer (12 triple negative and 16 HER-2 positive). One to 11 nodes were retrieved. Twenty-nine of 30 BxLN were successfully localized with RSL. Note was made of the BxLN-containing isotope and/or dye in 22 of 30. Nineteen patients had no residual axillary disease; 11 had persistent disease. All who remained node positive had disease in the BxLN. CONCLUSIONS: RSL/SLNB is a promising approach for axillary staging after NAC in patients whose disease becomes cN0. The status of the BxLN after NAC predicted nodal status, suggesting that localization of the BxLN may be more accurate than SLNB alone for staging the axilla in the cN0 patient after NAC.

Patterns of change in cognitive function with anastrozole therapy.

BACKGROUND: The purpose of this study was to examine and compare the effects of the first 18 months of anastrozole therapy on cognitive function in women with breast cancer. METHODS: This large, longitudinal cohort study was composed of postmenopausal women with early-stage breast cancer who received chemotherapy plus anastrozole (n = 114) or anastrozole alone (n = 173) and a control group (n = 110). Cognitive function was assessed before systemic therapy and 6, 12, and 18 months after therapy initiation and at comparable time points in controls. RESULTS: The chemotherapy-anastrozole and anastrozole-alone groups had poorer executive function than the controls at nearly all time points (P < .0001 to P = .09). A pattern of deterioration in working memory and concentration was observed during the first 6 months of anastrozole therapy for the chemotherapy-anastrozole group (P < .0001 and P < .0009, respectively) and the anastrozole-alone group (P = .0008 and P = .0002, respectively). This was followed by improved working memory and concentration from 6 to 12 months in both groups. The anastrozole-alone group had a second decline in working memory and concentration from 12 to 18 months after the initiation of therapy (P < .0001 and P = .02, respectively). CONCLUSIONS: Women with breast cancer had poorer executive functioning from the period before therapy through the entire first 18 months of therapy. A pattern of decline in working memory and concentration with initial exposure to anastrozole was observed. Women receiving anastrozole alone had a second deterioration in working memory and concentration from 12 to 18 months after therapy initiation. The longer term effects (>18 months) of anastrozole on cognitive function remain to be determined.

Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance).

OBJECTIVE: To evaluate factors affecting sentinel lymph node (SLN) identification after neoadjuvant chemotherapy (NAC) in patients with initial node-positive breast cancer. BACKGROUND: SLN surgery is increasingly used for nodal staging after NAC and optimal technique for SLN identification is important. METHODS: The American College of Surgeons Oncology Group Z1071 prospective trial enrolled clinical T0-4, N1-2, M0 breast cancer patients. After NAC, SLN surgery and axillary lymph node dissection (ALND) were planned. Multivariate logistic regression modeling assessing factors influencing SLN identification was performed. RESULTS: Of 756 patients enrolled, 34 women withdrew, 21 were ineligible, 12 underwent ALND only, and 689 had SLN surgery attempted. At least 1 SLN was identified in 639 patients (92.7%: 95% CI: 90.5%-94.6%). Among factors evaluated, mapping technique was the only factor found to impact SLN identification; with use of blue dye alone increasing the likelihood of failure to identify the SLN relative to using radiolabeled colloid +/- blue dye (P = 0.006; OR = 3.82; 95% CI: 1.47-9.92). The SLN identification rate was 78.6% with blue dye alone; 91.4% with radiolabeled colloid and 93.8% with dual mapping agents. Patient factors (age, body mass index), tumor factors (clinical T or N stage), pathologic nodal response to chemotherapy, site of tracer injection, and length of chemotherapy treatment did not significantly affect the SLN identification rate. CONCLUSIONS: The SLN identification rate after NAC was higher when mapping was performed using radiolabeled colloid alone or with blue dye compared with blue dye alone. Optimal tracer use is important to ensure successful identification of SLN(s) after NAC.

Developing in vitro models of human ductal carcinoma in situ from primary tissue explants.

Because there are currently no reliable predictors for progression of ductal carcinoma in situ (DCIS) to invasive disease, nearly all patients receive comprehensive therapy, leading to over-treatment in many cases. Few in vitro models for studying DCIS progression have been developed. We report here the successful culture and expansion of primary DCIS from surgical specimens using a conditional reprogramming protocol. Patients with percutaneous core-needle biopsy demonstrating DCIS were enrolled in a tissue banking protocol after informed consent was received. Fresh tissue was taken from lumpectomy or mastectomy specimens, mechanically and enzymatically dissociated, cultured in medium conditioned by irradiated mouse fibroblasts and supplemented with rho-associated protein kinase (ROCK) inhibitor, and characterized by immunocytochemistry. Out of 33 DCIS cases, 58% (19) were expanded for up to 2 months in culture, and 42% (14) were frozen immediately after mechanical dissociation for future growth. The cultures are almost exclusively composed of cytokeratin 8- and EpCAM-positive luminal and cytokeratin 14-, cytokeratin 5-, and p63-positive basal mammary epithelial cells, suggesting maintenance of heterogeneity in vitro. Furthermore, as assessed by luminal and basal marker expression, these cells retain their cellular identities both in the "conditionally reprogrammed" proliferative state and after conditioned media and ROCK inhibitor withdrawal. When grown to 100 % confluency, the cultures organize into luminal and basal layers as well as luminal compartments surrounded by basal cells. Primary cultures of DCIS derived directly from patient tissues can be generated and may serve as in vitro models for the study of DCIS.

Radioactive seed localization versus wire localization for lumpectomies: a comparison of outcomes.

OBJECTIVE: The purpose of this study was to compare outcomes of radioactive seed localization (RSL) versus wire localization using surgical margin size, reexcision and reoperation rates, specimen size, radiology resource utilization, and cosmesis as measures. MATERIALS AND METHODS: Patients who underwent RSL before segmental mastectomy from April 1, 2011, to March 1, 2012, for biopsy-proven cancer were selected. Each was matched using tumor size, type, and surgeon to a wire localization control case, resulting in 232 cases. Width of the closest surgical margin, reexcision rate, and reoperation rate were compared as were the ratios of tumor volume to initial surgical specimen volume and tumor volume to all surgically excised volume (including reexcisions and reoperations). Cosmetic outcome was analyzed by comparison of Harvard scores and specimen volume with breast volume. Radiology resource utilization was compared before and after RSL implementation. RESULTS: No significant differences between methods were found in closest surgical margin (RSL mean, 0.45 cm; wire localization mean, 0.45 cm; p=0.972), reexcision rate (RSL mean, 21.1%; wire localization mean, 26.3%; p=0.360), reoperation rate (RSL, 11.4%; wire localization, 12.7%; p=0.841), ratio of the tumor volume to initial surgical specimen volume (RSL mean, 0.027; wire localization mean, 0.028; p=0.886), ratio of the tumor volume to total volume resected (RSL mean, 0.024; wire localization mean, 0.024; p=0.997), or in clinical or computed cosmesis scores (clinical p=0.5; calculated p=0.060). There was a 34% increase in scheduled biopsy slot utilization, 50% savings in time spent scheduling, and a 4.1-day average decrease in biopsy wait time after RSL institution. CONCLUSION: RSL is an acceptable alternative to wire localization and offers significant improvements in workflow.

Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial.

OBJECTIVE: To determine the impact of tumor biology on rates of breast-conserving surgery and pathologic complete response (pCR) after neoadjuvant chemotherapy. BACKGROUND: The impact of tumor biology on the rate of breast-conserving surgery after neoadjuvant chemotherapy has not been well studied. METHODS: We used data from ACOSOG Z1071, a prospective, multicenter study assessing sentinel lymph node surgery after neoadjuvant chemotherapy in patients presenting with node-positive breast cancer from 2009 through 2011, to determine rates of breast-conserving surgery and pCR after chemotherapy by approximated biologic subtype. RESULTS: Of the 756 patients enrolled on Z1071, 694 had findings available from pathologic review of breast and axillary specimens from surgery after chemotherapy. Approximated subtype was triple-negative in 170 (24.5%), human epidermal growth factor receptor 2 (HER2)-positive in 207 (29.8%), and hormone-receptor-positive, HER2-negative in 317 (45.7%) patients. Patient age, clinical tumor and nodal stage at presentation did not differ across subtypes. Rates of breast-conserving surgery were significantly higher in patients with triple-negative (46.8%) and HER2-positive tumors (43.0%) than in those with hormone-receptor-positive, HER2-negative tumors (34.5%) (P = 0.019). Rates of pCR in both the breast and axilla were 38.2% in triple-negative, 45.4% in HER2-positive, and 11.4% in hormone-receptor-positive, HER2-negative disease (P < 0.0001). Rates of pCR in the breast only and the axilla only exhibited similar differences across tumor subtypes. CONCLUSIONS: Patients with triple-negative and HER2-positive breast cancers have the highest rates of breast-conserving surgery and pCR after neoadjuvant chemotherapy. Patients with these subtypes are most likely to be candidates for less invasive surgical approaches after chemotherapy.

Localizing high-risk lesions for excisional breast biopsy: a comparison between radioactive seed localization and wire localization.

BACKGROUND: Improved resolution and utilization of screening breast imaging has increased identification of nonpalpable high-risk lesions (HRL) and subsequent excisional breast biopsies (EBBs). Wire localization (WL), used most commonly for EBBs, may have shortcomings, including wire displacement, patient discomfort, limitations with incision planning and scheduling logistics. Radioactive seed localization (RSL) may overcome these drawbacks. The purpose of this study was to compare WL and RSL for EBBs for HRLs. METHODS: All single-site EBBs for HRL performed by four breast surgeons were retrospectively reviewed over two consecutive 1-year periods. Patients with cancer on percutaneous core biopsy (CB) were excluded. Clinicopathologic information, operative time, targeted lesion retrieval rate, and upstage rate were collected. RESULTS: A total of 324 EBBs for HRL were performed: 196 using WL and 128 using RSL. CB pathology was atypical hyperplasia in 56 % of WLs and 62 % of RSLs. The remaining pathologies were radial scar, papilloma, atypical papilloma or lobular carcinoma in situ. Mean age was 54 years. OR time was 27 ± 8 min for WL and 27 ± 7 min for RSL (p = 0.9). Upstage rate was 6 and 5 % for WLs and RSLs, respectively (p = 0.5). Targeted lesions were retrieved in 98 % of WL and 99 % of RSL (p = 0.5). SV was 37.2 ± 32.8 cm(3) and 25.7 ± 22.3 cm(3) for WL and RSL, respectively (p = 0.001). CONCLUSIONS: RSL is comparable to WL for EBB of HRLs with similar OR times and upstage rates. SV is significantly decreased with RSL and may translate into improved cosmetic outcomes without sacrificing the diagnostic accuracy of the EBB.

Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.

IMPORTANCE: Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies. OBJECTIVE: To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged. MAIN OUTCOMES AND MEASURES: The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease. RESULTS: Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%). CONCLUSIONS AND RELEVANCE: Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00881361.

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer.

Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptor-negative/HER2+ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER)+/HER2+ tumors demonstrate pathologic complete response in ∼ 8% of cases and is generally limited to weak-to-moderate ER+/HER2+ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2+ tumors. A list of HER2+ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2+ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score ≤10]/HER2+), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER+ [H-score 11-199]/HER2+), and Luminal A-HER2 Hybrid (LAHH; strong ER+[H-score ≥200]/HER2+). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2+ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting.

Molecular class as a predictor of locoregional and distant recurrence in the neoadjuvant setting for breast cancer.

BACKGROUND: The molecular subtype by hormone receptor status predicts recurrence in the adjuvant setting. Here, we report recurrence patterns by molecular subtype following neoadjuvant chemotherapy (NACT) to identify subgroups prone to recurrence. MATERIALS AND METHODS: We retrospectively analyzed 331 patients receiving NACT plus lumpectomy and whole breast radiation therapy (RT) (n = 155), or mastectomy with (n = 122) or without (n = 50) adjuvant RT. Tumors were classified by immunohistochemical (IHC) surrogate markers into luminal A (strong ER+/PR+; HER2-), luminal B (weak-to-moderate ER+/PR+; HER2-), HER2 (HER2+), and triple-negative/basal subtypes. RESULTS: The median follow-up was 43 months (range 10-104). The 5-year disease-free survival (DFS) was 71.4, 70.1, 70.4, and 62.1% for luminal A, luminal B, HER2, and basal subtypes, respectively. The 5-year distant recurrence rates were 25.8, 28.7, 28.7, and 35.2%. The 5-year locoregional recurrence rates were 3.8, 1.6, 1.3, and 4.2%. Molecular class (p = 0.003) and pathologic complete response (pCR; p = 0.004) predicted distant recurrence, DFS, and overall survival (OS). Only the omission of adjuvant RT following mastectomy (p = 0.006) predicted locoregional recurrence. CONCLUSIONS: IHC subclassification and pCR predict distant failure, DFS, and OS in the neoadjuvant setting. While not predictive of locoregional recurrence, the total number of events were small. More work is needed to define if molecular class can predict patients at risk for locoregional recurrence.

The pen and the scalpel: effect of diffusion of information on nonclinical variations in surgical treatment.

BACKGROUND: As information is disseminated about best practices, variations in patterns of care should diminish over time. OBJECTIVE: To test the hypotheses that differences in rates of a surgical procedure are associated with type of insurance in an era of evolving practice guidelines and that insurance and site differences diminish with time as consensus guidelines disseminate among the medical community. METHODS: We use lymph node dissection among women with ductal carcinoma in situ (DCIS) as an example of a procedure with uncertain benefit. Using a sample of 1051 women diagnosed from 1985 through 2000 at 2 geographic sites, we collected detailed demographic, clinical, pathologic, and treatment information through abstraction of multiple medical records. We specified multivariate logistic models with flexible functions of time and time interactions with insurance and treatment site to test hypotheses. RESULTS: Lymph node dissection rates varied significantly according to site of treatment and insurance status after controlling for clinical, pathologic, treatment, and demographic characteristics. Rates of lymph node dissection decreased over time, and differences in lymph node dissection rates according to site and generosity of insurance were no longer significant by the end of the study period. CONCLUSIONS: We have demonstrated that rates of a discretionary surgical procedure differ according to nonclinical factors, such as treatment site and type of insurance, and that such unwarranted variation decreases over time with diminishing uncertainty and in an era of diffusion of clinical guidelines.

Standardization of nodal radiation therapy through changes to a breast cancer clinical pathway throughout a large, integrated cancer center network.

BACKGROUND: Studies demonstrate safety of omitting axillary nodal dissection for early-stage breast cancer with positive sentinel lymph node (+SLN) biopsy, although trial designs differed in radiation therapy (RT) fields. Regional nodal irradiation was separately shown to improve outcomes in high-risk patients. This led to lack of consensus in RT volumes. Clinical pathways (CPs) standardize care where practice varies unnecessarily. We evaluated the impact of changes to a CP guiding postoperative RT in women with +SLNs on practice patterns throughout a network. METHODS AND MATERIALS: We implemented a CP for management of breast cancer with postoperative RT designed to promote uniform nodal treatment. The CP recommended modified tangents (MTs) including level I/II nodes for women with micrometastases (pN1mi). For women with macrometastases (pN1a), CPs recommended including level I/II LN in MT and a third supraclavicular node (SCN) LN ± internal mammary nodes for women with adverse factors present. RESULTS: RT fields of 233 women undergoing breast-conserving surgery with +SLN but not axillary nodal dissection were retrospectively reviewed: 25% had pN1mi disease and 75% pN1a. Of 127 women treated before CP changes, 35% with pN1mi and 22% with pN1a were treated with whole-breast irradiation alone. Following CP changes, 106 women were treated: 5% with whole-breast irradiation alone, 58% with MT, and 38% with MT + SCN field. Utilization of MT was associated with CP changes. Utilization of a third SCN field was associated with CP changes, pN stage, extracapsular extension, and total number of adverse factors. CONCLUSIONS: CPs translate published data and institutional experience into management plans that promote evidence-based care and eliminate unnecessary practice variations. Recognizing that postoperative RT treatment volumes were heterogeneous, we modified the CP based upon the latest evidence for regional nodal irradiation, after which we found increased compliance and consistency with quality guidelines, which will also aid in tracking outcomes in future investigations.

Is completion axillary lymph node dissection necessary in patients who are underrepresented in the ACOSOG Z0011 trial?

PURPOSE: The American College of Surgeons Oncology Group trial Z0011 demonstrated that axillary node dissection (ALND) can be omitted in patients managed with breast conserving surgery and 1 to 2 positive sentinel lymph nodes (SLNs) without adverse effects on locoregional recurrence or disease-free survival (DFS). We investigated patients with breast cancer for whom clinicopathologic features were underrepresented in the Z0011 trial and analyzed radiation therapy treatment patterns and clinical outcomes. METHODS AND MATERIALS: We retrospectively reviewed records of patients who underwent a lumpectomy and SLN biopsy with positive SLNs but not an ALND and completed adjuvant radiation therapy. Eligible patients had T3 tumors, >2 positive SLNs, invasive lobular carcinoma, estrogen receptor negative status, extranodal extension, Nottingham Grade 3, or were age <50 years. RESULTS: We identified 105 women treated between July 2011 and July 2016 with a median follow-up time of 48.5 months (Range, 11-83 months). There were 40 women with an extranodal extension (38.9%) and 42 women with grade 3 disease (40.0%). Nineteen patients received whole breast irradiation alone (18.1%) and 86 patients were treated with modified tangent fields including the superior axilla level I/II (81.9%). Thirty-three patients (31.4%) also received a 3rd supraclavicular, nodal-directed field. Among the 86 patients who received axillary nodal irradiation, nodal volume contouring was performed in 77 patients (89.5%). Fifty-one patients (48.6%) also received adjuvant chemotherapy. The overall rates of 4-year DFS and locoregional control (LRC) were 94.3% and 98.1%, respectively. Off all patients, 1 patient experienced an internal mammary nodal recurrence, another patient a contralateral breast tumor, and two patients distant metastases. There were no axillary or ipsilateral breast tumor recurrences. CONCLUSIONS: This retrospective analysis of women who were underrepresented or excluded from the Z11 trial and underwent a lumpectomy and SLN biopsy with positive SLNs demonstrated comparable rates of LRC and DFS. The high rates of LRC and DFS suggest that completion ALND may be safely omitted in this patient population but larger data sets and longer follow-up times are needed to confirm this finding.

Low Estrogen Receptor (ER)-Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease?

OBJECTIVES: Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. METHODS: Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. RESULTS: The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases. CONCLUSIONS: Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.